Metal-free oxidation/C(sp3)iH functionalization of unactivated alkynes using pyridine-N-oxide as the external oxidant

Article abstract of DOI:10.1002/anie.201205062

Externally yours: 2,3-Dihydroquinolin-4(1H)-ones are obtained in moderate to good yields (40-84 %, see scheme) in a metal-free oxidation/C(sp ³)iH functionalization of unactivated aryl alkynes. 2,6-Dichloropyridine-N-oxide is used as an external oxidant. In the reaction, a Bronsted acid, not a metal, plays a key role in the triple CiC bond activation. Copyright

Full text of DOI:10.1002/anie.201205062

Angewandte
Chemie
DOI: 10.1002/anie.201205062
À
C H Activation
3
À
Metal-Free Oxidation/C(sp ) H Functionalization of Unactivated
Alkynes Using Pyridine-N-Oxide as the External Oxidant**
Dian-Feng Chen, Zhi-Yong Han, Yu-Ping He, Jie Yu, and Liu-Zhu Gong*
3
3
À
À
The direct and selective functionalization of the C(sp ) H
bond has broad synthetic potential owing to the ubiquity of
this bond in organic compounds, but it’s transformation still
remains challenging.[1] In recent years, a 1,5-hydride transfer/
cyclization strategy giving a rapid buildup of molecular
complexity has drawn increased attention.[2] Electron-defi-
cient alkenes[3] were used as the most typical hydride accept-
ors under various conditions [Scheme 1, Eq. (1)] in the early
reports, although there were a few examples that deal with
a feasible new pathway for C(sp ) H functionalization.
Zhang, Houk and co-workers[12] have recently identified
a mechanism involving concerted 1,5-hydride/oxygen trans-
fer/cyclization to realize the formation of piperidinones and
azapanones [Scheme 2, Eq. (3)]. Despite these breakthroughs
using gold catalysis, there is interest in seeking metal-free
routes to these transformations, not only because these metals
are often expensive and environmentally hazardous, but also
residual metallic impurities are an important issue, especially
in pharmaceutical industry. Herein, we report a metal-
3
À
free oxidation/C(sp ) H functionalization of unacti-
vated terminal alkynes, yielding 2,3-dihydroquinolin-
4(1H)-ones as potential precursor to 4-quinolone
[Scheme 2, Eq. (4)], which is an important structural
motif of clinically used antibacterial drugs.[13] To our
knowledge, this finding is the first example involving
unactivated alkynes that does not require the partic-
ipation of a gold complex.[14]
On the basis of Zhangꢀs pioneering work,[15] we
À
initially investigated an oxidation/C H functionaliza-
tion cascade using 2-ethynylaniline derivative 1a as
a substrate in the presence of 5 mol% [PPh3AuNTf2]
(NTf2 = bis(trifluoromethylsulfonyl)amide) 2.0 equiva-
lents MsOH (methanesulfonic acid), and pyridine-N-
oxide 2a (in CH2Cl2, at 308C; Table 1, entry 1). After
the complete consumption of 1a in 12 h, the desired 2,3-
dihydroquinolin-4(1H)-one 4a was successfully isolated in
only 17% yield, meanwhile a byproduct 4b was isolated (only
in 15% yield). We suspected that the trace amount of H2O in
solvent probably led to the formation of 4b through the
competing hydroamination/hydrolysis reaction of alkynes.[16]
The yield of 4a was improved to 35% by using 2b as the
oxidant (Table 1, entry 2). Surprisingly, the reaction also
proceeded to give 4a in the absence of the gold complex
without a significant decrease in the yield (Table 1, entry 3 vs
entry 2).
3
À
Scheme 1. C(sp ) H functionalization by hydride transfer/cyclization sequen-
ces, EWG=electron-withdrawing group.
imines[4] or aldehydes.[5] Once efficient C(sp ) H functional-
3
À
ization of activated alkynes were demonstrated, the 1,5-
hydride transfer/ring-closure strategy became established in
the research area of alkynes [Scheme 1, Eq. (2)].[6] For
unactivated alkyne substrates, Ru,[7,8b] Pt,[8] Pd,[9] and Au[10]
were found to be the practical catalysts.
Recently, the rapid development of a-oxo gold carbene
species generated through oxidation of alkynes[11] provides
[*] D.-F. Chen, Dr. Z.-Y. Han, Y.-P. He, Dr. J. Yu, Prof. Dr. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
E-mail: gonglz@ustc.edu.cn
Homepage: http://staff.ustc.edu.cn/~gonglz/index.html
[**] We are grateful for financial support from the Chinese Academy of
Sciences, MOST (973 project 2009CB82530), the Ministry of
Education, and BASF (L.-Z.G.). We also thank the China Postdoc-
toral Science Foundation funded project (2011M501048), the
Fundamental Research Funds for the Central Universities
(WK2060190017), and the support of the K. C. Wang Education
Foundation, Hong Kong.
3
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205062.
Scheme 2. Oxidation/C(sp ) H functionalization of unactivated
alkynes under gold(I) and metal-free conditions.
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[a]
Table 1: Optimization of reaction conditions.[a]
Table 2: Scope for the metal-free oxidation/C H functionalization.
À
Entry Substrate
t [h] Product
Yield [%][b]
Entry
Cat.[b]
Oxide
Additive
Solvent
t
Yield [%][c]
[h]
4a
4b
1
2
3
4
5
6
7
8
9
1b: R3 =4-F
12
3
3
12
24
12
24
12
2
4b
4c
4d
4e
4 f
4g
4h
4i
75
71
65
84
51
48
56
76
72
1c: R3 =4-Cl
1d: R3 =4-Br
1e: R3 =4-OCF3
1 f: R3 =4-CF3
1g: R3 =5-F
1
2
3
4
5
6
7
8
[Au]
[Au]
–
–
–
–
–
–
–
–
–
–
–
–
-
-
2a
2b
2b
3a
3b
3c
3c
2c
2c
2c
2c
2c
2c
2d
2e
2d
MsOH
MsOH
MsOH
MsOH
TFA[d]
MsOH
MsOH[e]
MsOH[e]
TFA[e]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
MeCN
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
12
12
12
12
3
3
3
3
24
24
24
24
24
3
17
35
28
–
15
18
13
75
93
13
18
–
–
–
–
15
–
–
1h: R3 =5-CH3
1i: R3 =5-CF3
1j: R3 =3-F
40
53
53
trace
12
45
20
trace
72
64
–
4j
9
10
11
12
13
14
15
16
TfOH[e]
MsOH[e]
MsOH[e]
MsOH[e]
MsOH[e]
MsOH[e]
–
10
11
24
24
40
50
–
–
–
3
48
[a] Unless indicated otherwise, reactions of 1a (0.2 mmol), 2, or 3
(0.4 mmol) and additive (0.4 mmol) were carried out in 2 mL solvent at
308C, best result highlighted in bold. [b] [Au]=[Ph3PAuNTf2]. [c] Yield of
isolated product. [d] Under the same conditions, 1a would not be
consumed when using MsOH. [e] 4.0 equivalents were used.
1m: R3 =H
1n: R3 =4-Cl
1o: R3 =4-F
2
2
2
4m
4n
4o
56
42
52
This finding prompted us to develop a metal-free proce-
dure. Thus, a range of sulfoxide and N-oxides were examined
as external oxidants (Table 1, entries 4–8). Phenyl sulfoxide
(3a) and N-methyl morphine-N-oxide (3b) led to exclusive
production of 4b. The yield of 4a was improved to 53% in the
presence of 4.0 equivalents of MsOH when 8-methylquino-
line-N-oxide (3c) was employed (Table 1, entry 7). 3,5-
Dibromopyridine-N-oxide 2c turned out to work better
than 3c on account of it suppressing the formation of 4b.
Both TFA and TfOH failed to give a decent yield (Table 1,
entries 9, 10). Of the solvents used, CH2Cl2 was found to be
the solvent of choice (Table 1, entries 11–14). Another two
different substituted pyridine-N-oxides 2d and 2e were then
investigated (Table 1, entries 14, 15), and the yield was
substantially improved to 72% when 2d was used. Moreover,
the starting substrate was recovered almost quantitatively
even after 48 h in the absence of MsOH (Table 1, entry 16),
clearly demonstrating the significant nature of MsOH
towards activation of alkynes.[17]
With the optimized conditions in hand, we investigated
the generality of this metal-free method (Table 2). The
Brønsted acid promoted reaction tolerated a range of 2-
ethynylanilines bearing either of electron-withdrawing, neu-
tral, or electron-donating substituents on the benzene ring
(Table 2, entries 1–9), affording the products in 48–84%
yields. Notably, 2-ethynylanilines with biologically active
fluorine-based substituents underwent the reaction cleanly
12
13
14
15
12
(30%)
(25%)
[a] Unless indicated otherwise, reactions of 1 (0.2 mmol), 2d
(0.4 mmol), and MsOH (0.8 mmol) were carried out in 2 mL CH2Cl2 at
308C. [b] Yield of isolated product.
(Table 2, entries 1,4–6,8,9). More importantly, a range of
substituents including acyclic, cyclic, and unsymmetric var-
iants on the amine moiety were amenable, leading to the
formation of the corresponding products in moderate yields
(40–56%; Table 2, entries 10–15, the result in entry 15 was
considered as 55% yield in total). Compared to the reactions
exploring 1l and 1p, 4l was produced exclusively, whereas 4p
and 4p’ were obtained in 55% total yield albeit with
indistinctive regioselectivity.[18] In addition, a preliminary
enantioselective method was investigated with a chiral phos-
phoric acid, but with a low enantioselectivity.[19]
We have endeavored to probe the mechanism of this
metal-free route. As part of deuterium-labeling studies, 1a
was added to the reaction under standard conditions except
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that 4.0 equivalents of MsOD was employed [Scheme 3,
Eq. (5)]. Combined with [D1]-4aꢀs tolerance of MsOH[20]
[Scheme 3, Eq. (6)], the observation of 50% deuterium on
Scheme 3. Deuterium-labeling experiments (1).
[D1]-4aꢀs ketonic a-position implied that protonation of
alkynes occurred in the initial step. Then [D4]-1m which
was 100% deuterated at methylene positions adjacent to
nitrogen was prepared to trace the potential hydride transfer.
The reaction afforded a 50% yield of [D3]-4m with no
deuterium at ketonic a-position [Scheme 4, Eq. (7)], which
probably went through a hydride-transfer/elimination pro-
cess.[21]
Scheme 6. Reaction mechanism.
On basis of the above observations, a mechanism was
proposed (Scheme 6). In the initial step, the basic nitrogen
atom tends to capture a proton,[22] which would promote the
protonation of alkynes. Intermediate A is formed by dear-
omatization of styrene cation. Afterwards, there are two
possible pathways that account for the formation of the final
products. In path a, the nucleophilic attack of pyridine-N-
oxide onto A generates enolate B, which undergoes a sub-
sequent 1,5-hydride transfer/ring-closure process that is
probably promoted by delocalization of B, though there is
no conclusive evidence. In a final intermediate D, the
interaction between methanesulfonic anion and pyridine
[21]
Scheme 4. Deuterium-labeling experiments (2).
À
À
cation would facilitate C H and N O bonds cleavage.
The above-mentioned rearrangement in intermediate D not
only rationalizes the formation of corresponding product, but
also explains the deuterium loss of [D3]-4m [Scheme 4,
Eq. (7)]. In an alternative path b, the hydride of intermediate
A would migrate preferentially to facilitate the cyclization
and the consequential nucleophilic attack of pyridine-N-oxide
onto benzylic cation C. According to our previous control
experiments, path a seems to be more likely, while path b
cannot be ruled out.
Some control experiments were also established. Under
optimized conditions, BnNEt3Cl was chosen as a new nucle-
ophile instead of pyridine-N-oxide 2d, furnishing a simple
styrene derivative 5 [Scheme 5, Eq. (8)]. This reaction super-
ficially proceeded through a direct addition of HCl to 1a
whereas complete hydrolysis of phenylacetylene under same
conditions was observed [Scheme 5, Eq. (9)], which made us
suspect the formation of a nitrogen-involved intermediate A
via dearomatization. Accordingly, we would like to envisage
that pyridine-N-oxide attacks intermediate A prior to its
internal hydride-transfer process, , however, further evi-
denced for this proposal has not been found.
In summary, we have demonstrated the metal-free
3
À
oxidation/C(sp ) H functionalization of unactivated aryl
alkynes using pyridine-N-oxide as an external oxidant,
revealing that the Brønsted acid MsOH plays an extremely
important role in promoting this reaction. We have also
preliminarily suggested a mechanism in which a key inter-
mediate A is identified and two possible pathways are
proposed to rationalize the formation of the final products.
Further efforts to advance the understanding of the mecha-
nism and investigations focused on high enantioselective
process are underway.
Experimental Section
2-Ethynylaniline derivatives 1 (0.2 mmol) and 2,6-dichloropyridine-
N-oxide 2d (0.4 mmol) were dissolved in CH2Cl2 (1.0 mL) in a dried
Scheme 5. Control experiments.
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test tube. A solution of MsOH (0.8 mmol) in CH2Cl2 (1.0 mL) was
added to the mixture at 308C and the stirring was continued until
1 was consumed completely. Then NEt3 (0.2 mL) was introduced to
the mixture to quench the reaction. After evaporation of all volatiles
under vacuum, the residue was purified through column chromatog-
raphy on silica gel (eluting with petroleum ether/ethyl acetate 20:1) to
afford 4.
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Received: June 28, 2012
Revised: August 26, 2012
Published online: October 26, 2012
À
Keywords: Brønsted acid · C H functionalization ·
hydride transfer · metal-free reactions · oxidation
.
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